rs1800014

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000311.5(PRNP):c.655G>A(p.Glu219Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.004 in 1,613,590 control chromosomes in the GnomAD database, including 198 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0031 ( 18 hom., cov: 32)

Exomes 𝑓: 0.0041 ( 180 hom. )

Consequence

PRNP
NM_000311.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:6

Conservation

PhyloP100: 1.04

Variant links:

Genes affected

PRNP (HGNC:9449): (prion protein (Kanno blood group)) The protein encoded by this gene is a membrane glycosylphosphatidylinositol-anchored glycoprotein that tends to aggregate into rod-like structures. The encoded protein contains a highly unstable region of five tandem octapeptide repeats. This gene is found on chromosome 20, approximately 20 kbp upstream of a gene which encodes a biochemically and structurally similar protein to the one encoded by this gene. Mutations in the repeat region as well as elsewhere in this gene have been associated with Creutzfeldt-Jakob disease, fatal familial insomnia, Gerstmann-Straussler disease, Huntington disease-like 1, and kuru. An overlapping open reading frame has been found for this gene that encodes a smaller, structurally unrelated protein, AltPrp. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

PRNP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00404042).

BP6

Variant 20-4699875-G-A is Benign according to our data. Variant chr20-4699875-G-A is described in ClinVar as [Benign]. Clinvar id is 13409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-4699875-G-A is described in Lovd as [Likely_benign]. Variant chr20-4699875-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00308 (468/151736) while in subpopulation SAS AF= 0.0552 (264/4786). AF 95% confidence interval is 0.0497. There are 18 homozygotes in gnomad4. There are 311 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 18 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRNP	NM_000311.5 linkuse as main transcript	c.655G>A	p.Glu219Lys	missense_variant	2/2	ENST00000379440.9	NP_000302.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRNP	ENST00000379440.9 linkuse as main transcript	c.655G>A	p.Glu219Lys	missense_variant	2/2	1	NM_000311.5	ENSP00000368752	P1	P04156-1
PRNP	ENST00000424424.2 linkuse as main transcript	c.655G>A	p.Glu219Lys	missense_variant	2/2	1		ENSP00000411599	P1	P04156-1
PRNP	ENST00000430350.2 linkuse as main transcript	c.655G>A	p.Glu219Lys	missense_variant	2/2	1		ENSP00000399376	P1	P04156-1
PRNP	ENST00000457586.2 linkuse as main transcript	c.655G>A	p.Glu219Lys	missense_variant	2/2	1		ENSP00000415284	P1	P04156-1

Frequencies

GnomAD3 genomes

AF:

0.00309

AC:

468

AN:

151618

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000291

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000526

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0332

Gnomad SAS

AF:

0.0553

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00802

AC:

2016

AN:

251398

Hom.:

AF XY:

0.00934

AC XY:

1269

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0356

Gnomad SAS exome

AF:

0.0413

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.00424

GnomAD4 exome

AF:

0.00410

AC:

5987

AN:

1461854

Hom.:

180

Cov.:

AF XY:

0.00515

AC XY:

3745

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.00132

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0500

Gnomad4 SAS exome

AF:

0.0415

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000656

Gnomad4 OTH exome

AF:

0.00457

GnomAD4 genome

AF:

0.00308

AC:

468

AN:

151736

Hom.:

Cov.:

AF XY:

0.00420

AC XY:

311

AN XY:

74124

show subpopulations

Gnomad4 AFR

AF:

0.000290

Gnomad4 AMR

AF:

0.000526

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0330

Gnomad4 SAS

AF:

0.0552

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000589

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00220

Hom.:

Bravo

AF:

0.00211

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00875

AC:

1062

Asia WGS

AF:

0.0450

AC:

155

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 05, 2022	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Feb 01, 2012

- -

Inherited prion disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Huntington disease-like 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

T;T;T

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.82

.;T;T

MetaRNN

Benign

0.0040

T;T;T

MetaSVM

Benign

-0.74

MutationAssessor

Benign

0.0

N;N;.

MutationTaster

Benign

0.97

N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

0.0

N;N;N

REVEL

Benign

0.19

Sift

Benign

0.035

D;D;D

Sift4G

Benign

0.090

T;T;T

Polyphen

0.0050

B;B;.

Vest4

0.17

MVP

1.0

MPC

0.55

ClinPred

0.0090

GERP RS

3.1

Varity_R

0.21

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over